Rant: Bigger is not always better

Get your mind out of the gutter!  I'm talking about hydrocortisone dosing.

I have hundreds of papers saved, all of which I've thought important at one time or another, most of which I have not read in their entirety.  I came across Effect of Dose Size on the Pharmacokinetics of Oral Hydrocortisone Suspension by Toothtaker, Craig and Welling.  

This is a highly technical study.  I will summarize the high points as I understand them.  Please pull this study and have a read!  Above, I've included a link to the abstract.  

I tend to have a lot of criticisms of studies but this one seemed pretty straight forward.  I'm sure someone with more knowledge of pharmacology could tear this apart.  Read on for my interpretation and quotes from the study.

1. "The elimination half-life was affected by dose size,..."
1. 5 mg 1.2 hours (72 minutes)
2. 10 mg 1.3 hours (78 minutes)
3. 20 mg 1.5 hours (90 minutes)
2. "The drug is absorbed rapidly into the circulation, achieving peak plasma concentrations within 1 hour."
3. "An overall five-fold increase in the tablet dose (10-50 mg) resulted in a 2.1 fold increase in mean C max [peak plasma concentration]..."
4. "A number of explanations was originally proposed to account for the nonporportional relationship between circulating hydrocortisone levels and the size of the oral dose."  The researchers eliminated several reasons and came up with "An increased free fraction during first-pass is likely to permit greater hepatic clearance, and to decrease the systemic availability of unchanged drug."  My interpretation:  your liver can only process so much hydrocortisone at one time.
5. "...the systemic availability of hydrocortisone is..."
1. 5 mg dose 71%  
2. 10 mg dose 57%
3. 20 mg  dose 56%
4. 30 mg  dose 40%
5. 50 mg  dose  40%
6. MY INTERPRETATION
1. You take a 5 mg dose and get 3.55 mg of cortisol out of it*
2. You take a 10 mg dose and get 5.7 mg of cortisol out of it*
3. You take a 20 mg dose and get 11.2 mg of cortisol out of it*
4. You take a 30 mg dose and get 12 mg of cortisol out of it*
5. You take a 50 mg dose and get 20 mg of cortisol out of it*

What can we, people on hydrocortisone, take away from this?  Bigger is not better.  Taking a 50 mg dose of hydrocortisone will NOT give you ten times more cortisol circulating in your blood.  Take smaller doses, more often to get the most out of your hydrocortisone dosing. 

Does your doctor have you on 30 mg of hydrocortisone/day all at once?  If so, you're not getting as much cortisol out of your dose as you could!  According to this study, you're getting about 12 mg of cortisol in your blood all at once instead of spread out through out the day.

In a more efficient scenario of 30 mg of hydrocortisone per day dosed 10/5/5/5/5 you'd be getting 19.9 mg of cortisol in your blood.  HUGE difference!

Many doctors subscribe to "less HC is better" and put patients on stupid, low doses which keep the patients from having any quality of life.  Physicians pay little mind to the pharmokinetics of hydrocortisone.  I can't blame them, it's a pretty obscure bit of science for an obscure disease.   Endogenously produced cortisol is about 10 - 15 mg per day (depending upon the source of reference).  If a doctor is fixated on these numbers and wants you to take an equivalent amount of oral hydrocortisone to the endogenously produced amount, you are screwed.  However, if you are taking 20 mg of oral hydrocortisone in doses of 10/5/5, you are coming in right in the ballpark at 12.87 mg of cortisol available in your blood!  Take 20 mg all at once and you get less, 11.2 mg of cortisol available in the blood.

Once again, physiologic dosing of hydrocortisone is best.  Smaller doses are more efficiently processed by the liver.  Smaller doses don't last as long (5 mg=72 minutes vs 10 mg=78 minutes) but if you are taking smaller doses more often, you won't feel ups and downs.  

How can this information be helpful in other ways?  Perhaps tapering hydrocortisone doses after an illness can be managed by talking smaller doses more often and less cortisol during each day of the taper?  If you don't feel great on the dose of hydrocortisone you're on, there is the possibility that changing the SIZE of your doses could help you feel better.  Taking smaller doses of hydrocortisone more often will provide you with smoother and greater hydrocortisone coverage (better blood sugar, blood pressure and energy).  If you're hyperpigmented and take large doses of HC throughout the day, hmmmmm, maybe that's your problem.  Very little cortisol is in your blood (less than your doctor thinks!) and it's triggering your pituitary to make lots of ACTH which will cause you to be hyperpigmented.  

Bigger is NOT always better!

*under ideal circumstances, your small intestine (where hydrocortisone is absorbed when you take it orally) health may vary